VraSR Regulatory System Contributes to the Virulence of Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) in a 3D-Skin Model and Skin Infection of Humanized Mouse Model

The vancomycin-resistance associated sensor/regulator, two-component regulatory-system ( ), regulates virulence and the response of (SA) to environmental stress. To investigate the role of in SA skin and soft tissue infections (SSTI), we inactivated the of a clinical CA-MRSA ST30 strain by insertion...

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Bibliographic Details
Published in:Biomedicines 2021-12, Vol.10 (1), p.35
Main Authors: Barua, Nilakshi, Yang, Ying, Huang, Lin, Ip, Margaret
Format: Article
Language:English
Subjects:
3D Skin model
Animal models
Antibiotics
Apoptosis
Bacteria
Collagen
Drug resistance
Environmental stress
Ethics
Fibroblasts
humanized mouse model
Internalization
Laboratory animals
Methicillin
MRSA
Skin
skin and soft-tissue infections
Skin diseases
Skin lesions
Staphylococcus aureus
Staphylococcus infections
Strains (organisms)
Tumor necrosis factor-TNF
Umbilical cord
Vancomycin
Virulence
VraSR regulatory system
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Summary:The vancomycin-resistance associated sensor/regulator, two-component regulatory-system ( ), regulates virulence and the response of (SA) to environmental stress. To investigate the role of in SA skin and soft tissue infections (SSTI), we inactivated the of a clinical CA-MRSA ST30 strain by insertional mutation in gene using the TargeTron-Gene Knockout System. We constructed an organotypic keratinocyte fibroblast co-culture (3D-skin model) and a humanized mouse as SSTI infection models. In the 3D-skin model, inactivation of in the strains ST30 and USA300 showed 1-log reduction in adhesion and internalization ( 0.001) compared to the respective wildtype. The mutant strains of ST30 ( 0.05) and USA300-LAC ( 0.001) also exhibited reduced apoptosis. The wildtype ST30 infection in the humanized mouse model demonstrated increased skin lesion size and bacterial burden compared to BALB/c mice ( 0.01). The response of the humanized mouse towards the MRSA infection exhibited human similarity indicating that the humanized mouse SSTI model is more suitable for evaluating the role of virulence determinants. Inactivation of in ST30 strain resulted in decreased skin lesion size in the humanized mouse SSTI model ( 0.05) and reduction in apoptotic index ( 0.01) when compared with the wildtype. Our results reveal that inactivating the system may be a potent anti-virulence approach to control MRSA infection.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines10010035